Most orange cats are male, while calico cats are female? Scientists find the key reason →

Compiled by: Gong Zixin

Image source: pixabay

No need to ask

Don't look at the tail.

You might easily guess that it is a male cat

That's right

Most orange cats are male

It's a quirk of feline genes

This also explains why almost all

Both calico and tortoiseshell cats are female

Scientists, curious about sex differences in cats, or simply out of love for cats, have spent more than 60 years searching in vain for the gene responsible for orange fur and the striking patchwork of colors seen in calico and tortoiseshell cats. Now, two independent research teams have found the long-awaited mutation and discovered a protein that has never been seen before in any animal that influences hair color .

“I’m absolutely convinced this is the gene,” said Carolyn Brown, a geneticist at the University of British Columbia who was not involved in either study. “I’m very happy about this. I’ve always wanted to know the answer to this question.”

Scientists have long been fascinated by tortoiseshell and calico cats: They are the offspring of black and orange cats and are almost always female, suggesting that the gene variant that makes the coat orange or black is located on the X chromosome . Male offspring of black and orange cats are usually monochromatic because they inherit only one X chromosome from their parents. For example, we can guess that Garfield's mother is orange because he inherited his only X chromosome from her.

But the mother cat inherits one X chromosome from each parent. Cells don't normally need both, so during embryonic development, each cell randomly chooses one X to express genes. The other chromosome curls up into a barely-moving ball—a phenomenon known as X inactivation . As a result, tortoiseshell cats end up with varying shades of black and orange fur, depending on which chromosome is inactivated in their skin. Calico cats add white fur to the mix because they have a second, unrelated genetic mechanism that blocks the production of pigment in certain cells.

I came across a calico cat while walking, and I was a little excited

In most mammals, including humans, red hair is caused by mutations in a cell-surface protein, Mc1r, that determines whether melanocytes produce dark pigment or lighter red-yellow pigment in the skin or hair . Mutations that make Mc1r less active can cause melanocytes to get "stuck" producing light pigment.

But the gene that encodes Mc1r doesn’t seem to explain where cats get their orange fur. It’s not on the X chromosome in cats or any other species, and most orange cats don’t have the Mc1r mutation. “It’s a genetic mystery, a puzzle,” says Greg Barsh, a geneticist at Stanford University.

To address this question, Barsh's team collected skin samples from four orange and four non-orange fetuses from cats at a spay/neuter clinic. To determine how individual skin cells express genes, the researchers measured the amount of RNA produced by each melanocyte and identified the gene it encodes. They found that orange cat melanocytes produced 13 times more RNA from a gene called Arhgap36, which is located on the X chromosome, than normal cats , leading the team to believe they had the key to orange color.

But when the researchers looked at the Arhgap36 gene sequence in orange cats, they didn't find any mutations in the DNA that encodes the Arhgap36 protein. Instead, they found that orange cats were missing a nearby stretch of DNA that doesn't affect the protein's amino acid composition but may be involved in regulating the amount of amino acids produced by cells. Barsh's team then scanned a database of 188 cat genomes and found that every orange, calico, and tortoiseshell cat had the exact same mutation . The team reported the findings in a preprint on bioRxiv.

Another study published last month on bioRxiv confirmed these findings. Developmental biologist Hiroyuki Sasaki of Kyushu University in Japan and his colleagues conducted similar experiments and found the same gene deletion in the genomes of 24 wild and pet cats in Japan and 258 cats collected from around the world. They also found that orange areas of calico cats' skin contained more Arghap36 RNA than brown or black areas . In addition, the Arhgap36 gene in mice, cats and humans acquired a chemical modification that silenced it on one of the two X chromosomes in females, the team documented, indicating that the gene is affected by X inactivation.

Barsh and Sasaki's respective teams discovered the same mutation, and both groups further found that increasing the amount of Arhgap36 in melanocytes activates a molecular pathway that causes the cells to produce a light red pigment, regardless of whether MC1r is active.

No one had previously known that Arhgap36 could affect skin or hair color—it's involved in many aspects of embryonic development, and major mutations that affect its function throughout the body would likely kill an animal, Barsh said. But because the deletion mutation appears to affect Arhgap36 function only in melanocytes , cats with the mutation are not only healthy, but cute.

Brown noted that the pattern of inactivation of Arhgap36 in calico and tortoiseshell cats is typical of genes on the X chromosome, but unusually, a deletion mutation makes a gene more active, not less . “There may be something special about cats,” he said.

Experts are excited about the two studies. Leslie Lyons, a feline geneticist at the University of Missouri, said the discovery of a new molecular pathway for coat color was unexpected, but she was not surprised by how complex the interactions are because no single gene exists in isolation.

Lyons wants to know when and where the mutation first arose. There is some evidence that some Egyptian cat mummies were orange, she said. Studies of cat color reveal a variety of phenomena, including how the environment affects gene expression. "Everything you know about genetics may be learned from the cats around you." This discovery is not only important for cat genetics research, but may also contribute to understanding the genetic mechanisms of coat color in other species.

Original author: Sara Reardon

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